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United States Patent SUBSTITUTED AZACYCLOOCTANES AND PROCESSCorporation, New York, N. Y., a corporation of Delaware No Drawing.Application January 6, 1954, Serial N0. 402,585

7 Claims. (Cl. 260-239) This invention relates to cyclic compounds andmore particularly involves azacycloalkanes and the method for preparingthem.

The application is a continuation-impart of application Serial No.297,185, filed July 3, 1952 now Patent No. 2,666,050.

The preparation of the compounds involves as a first step the alkylationof a 2-aryl-4-dialkylamino butyronitrile with a polymethylene sulfonicacid ester or halide having 4 to 8 methylene groups, this reaction beingcarried out in the presence of an active hydrogen reagent. Following thealkylation reaction, the product obtained is cyclicized, utilizing aninert high boiling solvent. The cyclic compound produced is hydrolyzedand then esterified to prepare the carbalkoxy compound, or thecyanoazacycloalkane is reacted with an alkyl Grignard or alkyl-lithiumand then hydrolyzed to form an acyl azacycloalkane.

The following reactions will illustrate the process steps:

lalkylatio'n C Hr (C H2) 1; C HrHalo l cyclization C N Ra R I g l P.O HCH N -R Hr (0 Hz) ,v 0&1

Hydrolysis and esteriflcatlon or I Organo-metallic addition andhydrolysls r! CC In the above formulae, R is intended to represent anaryl radicaL'specifically a substituted or unsubstituted phenyl or anaphthyl or benzhydryl radical. Preferred substitutents 'on a ring,which may be in any position and ranging from one to three, are loweralkyl, lower alkoxy, halogen, nitro, hydroxy, aliphatic acyl andacyloxy, amino and mono and di-lower alkyl-substituted amino radicals.

The radicals R1 and R2, which may be either similar or dissimilar toeach other, are intended to stand for lower alkyls and preferably alkylsof 1 to 4 carbon atoms. The radicals R3 and R4 may represent eitherhydrogen, methyl or ethyl groups.

With regard to the di-halo-alkane reactant, the designation halo isintended to stand for either chlorine, bromine or iodine. It may benoted that both halogen groups may be similar, i. e., both standing forbromine, for example, or they may be dissimilar, i. e., one standing forbromine, for example, and the other for chlorine.

The radical R represents a lower alkyl ester or lower aliphatic acylgroup connected to the'ring carbon at the carbonyl carbon, with thealkyl group preferably having no more than 3 carbon atoms.

The designation n is intended to stand for a whole number, from 2 to 6inclusive.

The starting compounds meeting the qualifications noted hereinabove,which may be prepared by well-known procedures, are reacted in thepresence of an active hydrogen reactant, preferably an alkali metalamide such as sodium, potassium or lithium amide although phenylsodium,phenyl-lithium or butyl-lithium are also operable. The reaction iscarried out in the presence of a solvent which may be either ethyl etheror an aromatic hydrocarbon such as benzene, toluene or xylene.Substantially anhydrous conditions should be utilized for best resultsand, while not necessary, an inert atmosphere, such as nitrogen gas, isdesirable for the reaction. The reaction goes easily at ordinarytemperatures, and, although room temperature or a temperature from about10 to 35 C. is preferred, one may operate in the broader range fromabout 10 C. to about 50 C.

Following the alkylation step the novel azacycloalkanes are prepared bya cyclization reaction carried out by heating the alkylated product inthe range of about 200 to about 250 C. If desired, an inert organicsolvent may be used, such solvent being selected with a boiling rangewithin the reactive temperature range noted and under refluxingconditions. .Tetralin, nitrobenzene, and especially the higher alcoholshave been found effective.

The alcohols, n-decyl alcohol, trimethyl nonyl alcohol and5-ethyl-2-nonyl alcohol are especialy suitabe as refluxing solvents.

On obtaining the cyclic aminonitrile, the latter may then be eitherhydrolyzed to an acid and then esterified, or

it may be changed to an acyl group'by alkyl-lithium or an alkyl Grignardfollowed by hydrolysis. To form the acid-ester, the aminonitrile ishydrolyzed under either acid or alkaline conditions. For acidhydrolysis, one may use any strong acid such as syrupy phosphoric acid,concentrated hydrobromic acid, etc., although -95% sulfuric acid ispreferred. Alkaline hydrolysis is also feasible, and, as an example,potassium hydroxide in an alkylene glycol will give the desired product.The hydrolysis reaction may be carried out at a temperature of about-150 C. with a more preferred range of about -120 C.

The cyclic acid or salt obtained as a product of the hydyrolysis step isthen esterified using a substantially anhydrous lower aliphatic alcohol,preferably one having no more than three carbon atoms and, morepreferably, using ethyl alcohol. The final cyclic ester may be obtainedby concentration of the esterification reaction off at atmosphericpressure, the cooled residue poured into mixture, neutralizing with anaqueous alkaline solution, an ice-cold saturated aqueous sodiumcarbonate solution, extracting the free base with a selective solventand finally then extracted with ether. The ether extract was dried,distilling 011 the solvent medium. filtered, and distilled giving theester base (III), B. P.

To form acyl-azacycloallcanes, one dissolves the nitrile 5 130133 C.(0.3 mm), 11 1.5215, da 1.042. in absolute ether and adds this solutionto Rs-MgBr or AnaL-Calcd. for C17H2502N: C, 74.18; H, 9.15; N, Rs-Li, inabsolute ether. R5 represents the radical indi- 5.08; M 80.70. Found: C,74.07; H, 9.06; N, 5.64; cated hereinabove. Immediate reaction occurs.The addi- M 80.68. tion reaction is completed by warming on a steam bathThe methiodide, M. P. l65167 C. dec., was formed and if necessary byreplacing the ether with toluene. The in a mixture of acetone and ether.reaction mixture is poured on ice in the presence of Amzl.-Calcd. forCraHzaOzNl; C, 51.82; H, 6.76; N, hydrochloric acid warmed gently tohydrolyze the imino 3.36; I, 30.5. Found: C, 51.92; H, 6.86; is, 3.09;I, 30.5. compound formed as an intermediate. The acyl-azacyclo- Theazacycloalkanes have numerous uses. One imalkane product is then in theaqueous layer and is obtained portant use is in the formation oflong-chain aliphatic by separating the two layers, making the aqueouslayer quaternary compounds which may be prepared in known alkaline andextracting with ether. The ether extract is manner by reacting thecycloalkanes with a long-chain then distilled to obtain the desiredproduct. aliphatic halide having from 8 to 18 carbon atoms, such As aspecific illustration of the process, the following as lauryl bromide,the temperature of reaction ranging procedure will serve to describe theinvention in greater from about 50 to about 150 C. Still another use ofdetail. 20 these alkylenimine compounds is in their ability to com-Syizr/zesis o 4-carbethoxy-4-plzenyl-1-methylazacyclooctane A solutionof 0.75 mole (141 g.) of 2-phenyl-4-dibine with penicillin to form saltstherewith, this procedure methylaminobutyronitrile in 300 ml. of etherwas added being useful in purifying penicillin and even obtainingdropwise to 0.90 mole (35.1 g.) of sodamide suspended therapeuticallyvaluable penicillin salts. in addition, an in 700 ml. of ether. Theoperations were carried out at analgesic action has been noted in anumber of com- C. under a nitrogen atmosphere with stirring. The pounds.The above uses apply equally to the free ascs mixture was refluxed 2hours, then cooled to 30 C. or their acid-addition salts.

A solution of 0.89 mole (153 g.) of tetramethylene chloro- Where it isdesired that the aryl radical include one or bromide in 300 ml. of etherwas added dropwise at more hydroxy-substituents on the ring. the abovede- -25 to -20 C. On completing the addition, the temscribed reactionsshould utilize corresponding alkoxyperature was gradually allowed torise to room tempera- 4:5 substituted compounds as reactants. After thealltoxyture and the mixture then stood overnight. The precipisubstitutedaryl-cyano-azacycloalkane is formed, one may tated inorganic salts werefiltered off and the ether disconvert the alkoxy group to ahydroxy groupby dissolving tilled from the filtrate under vacuum. The liquid residuethe nitrile in 48% hydrobromic acid, heating until contained the1,7-aminochloride (1). evolution of alkyl bromide begins. Thetemperature is One liter of trimethylnonanol was added to the residue 50maintained until reaction is completed, after which the and theresulting solution then added dropwise to 1 liter excess acid is pumpedoff. The residue is then esterified of stirred, refluxingtrimethylnonanol (B. P. 225 C.) by addition of alcohol and sulfuric acidand heating to during 1.5 hours. The solution was stirred and refluxedrefluxing overnight. The solution is then poured on ice an additional 2hours then cooled under a nitrogen atand the sulfuric acid catalyst isremoved by shaking mosphere. Dilute hydrochloric acid was used toextract with excess barium carbonate. The inorganic salts are out theamine. The acid extract was washed with ether, filtered off and thefiltrate is concentrated to dryness. then basified with sodium hydroxidesolution, and ex- The product may be recrystallized from alcohol.tracted with ether. The ether extract was dried, filtered, Theacid-addition salts which may include the salts of and evaporated downto leave a red viscous syrupy resithe inorganic or carboxylic acids maybe prepared in the due. The cyano base (Ii) was distilled away from alarge manner described in application Serial No. 297,185. mass ofresinous material at 140-160" C. (0.3-0.4 mm.). Acids of the typeindicated in said latter application yield Redistillation gave a yellowliquid, B. P. l30134 C. preferred salts.

(03111111.),I1 1.527Q,d4 1.010. The therapeutically useful compounds,more particu- Anal.Calcd. for C15H20N2Z C, 78.90; H, 8.82; N, larlythose possessing analgesic action, may be utilized 12.75; M 69.54.Found: C, 79.06; H, 9.32; N, 12.57; either orally, in suppository formor parenterally. For

M 69.48. oral use, the compounds may be combined in known The picrate,M. P. l58-59 C., was formed in acetonemanner in the form of an elixir orother liquid form with methanol. excipients, such as suspending andflavoring agents. They AnaL-Calcd. for Carl-123N507: C, 55.18; H, 5.07;N, may also be utilized in dry form, combined in the usual 15.32. Found:C, 55.33; H, 4.89; N, 15.13. way with binding agents, sugars and otherexcipients for A mixture of 0.04 mole (9.1 g.) of the cyano base (II),tablet or capsule form.

10.6 g. of 98% sulfuric acid, and 2.6 g. of water was We claim:

heated at 115-130 C. during 3 hours. The mixture was 1. The processcomprising heating a 3-phenyl-3-cyanocooled somewhat, ml. of absoluteethanol added, and 1-di-loweralkylamino-omega-haloheptane, to atemperathe mixture refluxed overnight. The alcohol was distilled 75 turein the range of about 200 to about 250 C., said heating being carriedout under refluxing conditions utilizing an inert organic solvent,thereby forming an azacyclooctane reaction product.

2. The process of claim 1, wherein the inert solvent is a higheraliphatic alcohol.

3. A compound selected from the group consisting of a heterocyclic basehaving the formula 4-cyano-4-phenyl-l-methyl- 7. As a new product,4-carbethoxy-4-phenyl-l-rnethylazacyclooctane.

References Cited in the file of this patent UNITED STATES PATENTSDiamond et al J an. 12, 1954 FOREIGN PATENTS Germany Mar. 25, 1935

3. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF A HETEROCYCLIC BASEHAVING THE FORMULA